Obesity and diabetic conditions are complex multifactorial syndromes that develop from an interaction between genetic and environmental factors. The GI tract and, in particular, GI regulatory peptides represent an ideal starting point for investigating nutrition-related disorders since the former represents the route by which all nutrients are processed and absorbed. In addition to its effects on islet beta-cell insulin release, we have recently identified receptors to glucose-dependent insulinotropic polypeptide (GIP) on human adipocytes. We have also found that a GIP-specific receptor antagonist developed in our laboratory inhibits binding of this peptide to fat cells. Moreover, we have observed that GIP inhibits isoproterenol-induced lipolysis in rat adipocytes, consistent with the hypothesis that GIP is functioning physiologically to enhance lipid deposition. Thus, it appears plausible that by antagonizing the adipocyte GIP receptor, the storage of lipid, and thereby obesity, might be prevented. However, neither the precise effects of GIP on adipocyte function nor the role of GIP in the pathogenesis of obesity have been determined. Specific aims of this project are to: 1. Characterize the GIP receptor, including regulation of receptor expression, intracellular signaling in adipocytes, and the relationship of GIP to insulin in fat cells; 2. Ascertain the effects of a GIP antagonist on the development of obesity using rodent models; and 3. Determine GIP expression in normal, obese, and diabetic states, employing a novel, sensitive bioassay to measure GIP concentrations in different rodent models. The studies outlined in this proposal will help clarify the precise role of GIP in the pathogenesis of these common multifactorial disorders and its physiological role in regulating fat cell function. Moreover, owing to the critical functional relationship between GIP and insulin, a detailed analysis of the intracellular pathways mediating the biological properties of GIP will facilitate the determination of the precise relationship between these two peptide hormones, as well as the physiological and pathological significance of GIP and its importance in the regulation of fat and glucose homeostasis. Finally, these studies will enable us to ascertain whether an antagonist to the GIP receptor on the adipocyte, as well as possibly in other organs, might be useful for the prevention of lipid deposition and in the treatment of obesity.